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Hematology Block 1 > Anemias > Flashcards

Anemias Flashcards

1
Q

Explain the hemoglobin measurement in a CBC:

A

Results give the concentration of hemoglobin; directly measured

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2
Q

Explain the hematocrit measurement in CBC:

A

Volume of red cells per total volume of blood, given as a percentage; calculated value

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3
Q

Hematocrit = ___ x ____

A

RBC x MCV

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4
Q

In general, hematocrit is about ___x the hemoglobin

A

3x

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5
Q

MCV:

A

Direct measurement of red cell volume in femtoliters; basically gives size

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6
Q

MCH:

A

Mean corpuscular hemoglobin

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7
Q

MCHC:

A

Mean corpuscular hemoglobin concentration

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8
Q

RDW:

A

Red cell distribution of width. Coefficient of the variation of the MCV. It’s how much “spread” there is in the MCVs of all the different red cells in the patient’s body

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9
Q

Define Anemia:

A

A decreased hemoglobin/hematocrit below the normal range for gender and age

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10
Q

Anemia is a ____ of disease, not a ____

A

is a manifestation of disease, not a final diagnosis

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11
Q

Anemia leads to reduction of ____ carrying-capacity

A

oxygen

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12
Q

Acutely, blood loss can lead to ____ blood volume

A

low

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13
Q

chronically, anemia can lead to ____ blood volume

A

increased (because it leads to fluid retention)

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14
Q

Most symptoms of acute hemorrhage are related to _____. List symptoms.

A

Related to hypovolemia, e.g. hypotension, orthostatic changes, syncope, and shock.

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15
Q

Symptoms of tissue ____ may be felt in anemic patients (list symptoms)

A

Tissue hypoxia. E.g. fatigue, SOB, cognitive difficulties, and ischemic pain

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16
Q

Describe two common responses to acute anemia due to blood loss:

A

Increased heart rate (increased cardiac output) and vasoconstriction

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17
Q

What is the body’s response to chronic anemia?

A

Kidneys retain salt and water to expand intravascular volume. Increased erythrocyte 2,3-DPG leads to right shift in O2 dissociation curve, and renal mesangial cells increase erythropoietin synthesis.

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18
Q

What are 3 most common mechanisms of anemia?

A

Hemorrhage, decreased RBC survival (hemolysis), and decreased RBC production.

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19
Q

How is anemia classified?

A

By the erythropoietic response (i.e. reticulocyte count) and by the red cell size (i.e. the MCV) and the hemoglobin concentration

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20
Q

If reticulocyte count is elevated in an anemia patient, what does this tell you?

A

You expect to see some proliferation in body’s attempt to counteract anemia. This suggests problem is with destruction or loss of RBCs

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21
Q

If reticulocyte count is low in an anemia patient, what does this tell you?

A

Hypo-proliferative. This suggests problem with RBC production.

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22
Q

Define reticulocytes:

A

young red cells immediately released by the bone marrow as the end result of erythropoiesis

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23
Q

On Wright-Giemsa staining, reticulocytes are _______

A

polychromatophilic (gray-blue)

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24
Q

On supravital staining, reticulocytes have _____ remnants and are ______

A

have RNA remnants and are “reticulated” (look lacy)

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25
Q

Reticulocyte index:

A

RI = reticulocyte count x Hct/ideal Hct x 0.2

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26
Q

Absolute reticulocyte count:

A

retic (%) x RBC

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27
Q

If retic index is

A

<2% or <75,000. Suggests a hypoproliferative abnormality.

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28
Q

If retic index is >__% or absolute retic count is > _____, this suggests a good marrow response, suggesting the cause of anemia is either ____ or ______

A

>2% or >100,000. Suggests either caused by hemorrhage or hemolysis.

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29
Q

Microcytic anemia:

A

Low MCV (<80). Tends to reflect a problem with hemoglobin synthesis. Iron deficiency, thalassemia, lead poisoning, anemia of chronic disease, and sideroblastic anemias

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30
Q

Macrocytic anemia:

A

high MCV (>100). Can be megaloblastic (impairment of DNA synthesis) or non-megaloblastic.

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31
Q

Normocytic anemia:

A

either the marrow isn’t working well, there is a mixed problem, or there is a very acute problem. Most anemias present with normocytic anemia.

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32
Q

What are the two approaches to treating anemia?

A

Treat the underlying cause and transfusion

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33
Q

What 3 factors help determine whether or not to transfuse an anemic patient?

A

How symptomatic they are, if the underlying cause can be reversed, and if there is enough time to treat the underlying cause.

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34
Q

What hemoglobin value indicates transfusion?

A

TRICKED YA. There is no absolute hemoglobin value that should be a transfusion trigger. There are upper values that will be deemed too high for transfusion.

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35
Q

General indications FOR transfusion:

A

CV compromise (e.g. CHF, shock, angina), hypoproliferative anemia with no recovery, or anemic patient going into surgery (has potential for further blood loss)

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36
Q

What is a normal hemoglobin value?

A

12-16

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37
Q

General clinical features of hemolytic anemia:

A
  1. Jaundice
  2. Dark urine
  3. Pigmented gallstones
  4. Chronic ankle ulcers
  5. Splenomegaly
  6. Aplastic crisis associated with Parvovirus B19
  7. Increased folate requirement
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38
Q

Define hemolytic anemias:

A

A group of disorders characterized by decreased red cell lifespan (patient may not always be anemic, depending on the degree of marrow compensation)

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39
Q

Red cell abnormalities found post-splenectomy:

A

Target Cells

Acanthocytes

Schistocytes

Nucleated red cells

Howell-Jolly bodies

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40
Q

Parvovirus B19

A
  • Non-encapsulated DNA virus.
  • Infects and lyses and destroys RBC precursors in marrow, causing 7-10d halt to erythropoiesis.
  • Normal individuals have no significant hematologic effect, since RBCs have normal life span.
  • In pts with hemolytic anemias, loss of red cell production causes reticulocyte counts and hemoglobin values to plummet dramatically = Aplastic Crisis
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41
Q

How are hemolytic anemias classified?

A

By sites of red cell destruction

Acquired vs. congenital

By mechanism of red cell damage

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42
Q

How can HA’s be divided based on sites of RBC destruction?

A
  1. Extravascular Hemolysis - macrophages in spleen, liver, and marrow remove damaged or antibody-coated red cells
  2. Intravascular Hemolysis - red cells rupture within the vasculature, releasing free hemoglobin into the circulation
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43
Q

Laboratory evidence for Hemolysis:

A
  • Evidence for increased red cell production (elevated reticulocyte count in blood, erythroid hyperplasia in the bone marrow, deforming changes in bone)
  • Evidence for increased red cell destruction (biochemical consequences of hemolysis, morphologic evidence of red cell damage, reduced red cell lifespan)
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44
Q

Erythroid hyperplasia:

A

Expansion of the erythroid lineage

Myeloid:erythroid ratio is normally 3:1 (because WBCs generally have higher turnover than RBCs); this photo has 1:10 (RBC turnover rate ramps up so high to make up for loss)

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45
Q

Biochemical consequences of hemolysis in general:

A

Elevated LDH levels (lactate dehydrogenase - released after lysis of ANY cells)

Elevated bilirubin (byproduct of heme breakdown - when the bilirubin is fractionated, the portion that is elevated is the unconjugated bilirubin)

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46
Q

Biochemical consequences of intravascular hemolysis:

A

Reduced serum haptoglobin (Haptoglobin is a protein made in the liver that normally circulates with a 2 week half-life. When bound to free hemoglobin, half life is reduced to less than a minute. See a drop in serum haptoglobin in hemolytic patients.)

Hemoglobinemia

Hemoglobinuria

Hemosiderinuria

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47
Q

Congenital vs. acquired hemolytic anemia

A

Congenital - Hereditary spherocytosis (autosomal dominant), G6PD Deficiency (X-linked recessive)

Acquired - Warm antibody-mediated (AIHA), cold antibody-mediated, paroxysmal cold hemoglobinurea, drug related hemolysis, paroxysmal nocturnal hemoglobinuria

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48
Q

______ is the most common defect leading to anemia

A

Hereditary spherocytosis

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49
Q

Defect associated with hereditary spherocytosis is in WHAT

A

proteins of the membrane skeleton of RBCs, usually ankyrin

lipid microvesicles are pinched off in the spleen, causing decreased MCV in the affected cells and spherocytic change

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50
Q

What is the inheritance pattern of hereditary spherocytosis?

A

Autosomal dominant

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51
Q

MCHC levels are importantly elevated in what disease?

A

Hereditary Spherocytosis

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52
Q

How is hereditary spherocytosis diagnosed?

A

Increased Osmotic Fragility

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53
Q

Treatment for hereditary spherocytosis:

A

Folate supplementation

Splenectomy (will cause hemolysis to abate, but spherocytes will persist)

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54
Q

Without ____, red cells lyse and/or deform

A

Without adequate energy

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55
Q

How do RBCs get energy?

A

RBCs get energy via anaerobic glycolysis, usually via Embden-Myerhof pathway.

There is an alternative pathway called the Pentose Phosphate Shunt which begins with G-6-P. The rate-limiting enzyme here is G6PD.

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56
Q

Low G6PD activity results in low levels of ____ and reduced _______, which are required to protect hemoglobin from oxidative damage.

A

NADPH and reduced glutathione

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57
Q

In the absence of adequate reducing ability (provided by ____), oxidizing agents convert hemoglobin to _______, then denature it, causing it to precipitate as ________.

A

In the absence of adequate reducing ability (provided by G6PD), oxidizing agents convert hemoglobin to methemoglobin, then denature it, causing it to precipitate as Heinz bodies.

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58
Q

The spleen pinches off the Heinz body and the overlying membrane, leaving: (with G6PD deficiency)

A

a “bite cell” or “blister cell”

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59
Q

What is the inheritance pattern of G6PD?

A
  • Deficiency is X-linked.
  • In Africans with G6PD deficiency, mutant protein is unstable and loses activity as the red cell ages.
  • Mediterranean variant has baseline low activity.
  • In US, 10-14% of African-American men have this disorder.
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60
Q

What agents need to be avoided in patients with G6PD deficiency?

A

Oxidant agents, e.g.

Anti-malarials (quinine)

Sulfa drugs

Dapsone

Vitamin k

Fava beans

Naphtha compounds (mothballs)

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61
Q

In patients with G6PD deficiency, hemolysis is generally triggered by WHAT

A

drugs or infections

(anemia is maximal 7-10 days after exposure)

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62
Q

How do G6PD patients compensate for anemia?

A

by making reticulocutes despite drug concentration

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63
Q

•Immediately after a hemolytic episode, G6PD levels in African or African American (but not Mediterranean) pts may be normal, WHY?

A

The mature cells have been lysed, and only younger cells with normal G6PD levels are present.

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64
Q

How is G6PD diagnosed?

A
  • Jaundice usually present.
  • Lab Dx -
  • ­reticulocytes, ­ bili (total and indirect/unconjugated), ­ LDH
  • Low haptoglobin
  • Bite and Blister cells are seen on the peripheral smear
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65
Q

Broadly, how do acquired hemolytic anemias destroy RBCs?

A
  • Antibodies bind to red cell antigens, with or without complement fixation, leading to RBC destruction.
  • IgG-coated RBCs interact with Fc receptors on macrophages, leading to complete or partial phagocytosis, with spherocyte formation (extravascular hemolysis).
  • C3-coated red cells interact with C3 receptors on macrophages, with phagocytosis (extravascular hemolysis). Alternatively, complement cascade can be completed, with complement-mediated RBC lysis (intravascular hemolysis).
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66
Q

What is the hallmark of autoimmune hemolytic anemia?

A

Positive Coomb’s Test

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67
Q

Warm antibodies:

A

React with RBCs best at 37 degrees

DO NOT agglutinate red cells

IgG

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68
Q

Cold antibodies:

A

React best <32 degrees

Causes RBC agglutination

IgM

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69
Q

The Direct Coomb’s Test (DAT) tests for ____ and ___, which are bound WHERE?

A

Tests for IgG or C3

bound DIRECTLY on the RBCs

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70
Q

What is the pathophysiology of Warm Antibody Hemolytic Anemias?

A
  • IgG antibodies directed against RBC membrane surface molecules are formed
  • IgG antibodies coat RBCs, with or without C3 complement (Direct Coomb’s test is positive)
  • IgG-coated red cell membrane fragments engulfed by macrophages in RE system (usually spleen).
  • Spherocytes form.
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71
Q

What is the etiology of Warm Antibody Hemolytic Anemias?

A
  • Can be either primary or secondary to another disorder, such as a hematologic malignancy or another autoimmune disease such as lupus
  • Can be induced by drugs
72
Q

Clinical features of Warm Antibody Hemolytic Anemias:

A
  • Splenomegaly, jaundice usually present.
  • Depending on degree of anemia and rate of fall in hemoglobin, patients can have VERY symptomatic anemia or not
73
Q

What are the lab results of a patient with a Warm Antibody Hemolytic Anemia?

A
  • ­reticulocytes, ­ bili (total and indirect/unconjugated), ­ LDH
  • Low haptoglobin
  • positive Coomb’s test
  • SPHEROCYTES are seen on the peripheral smear
  • There can be an elevated MCHC.
74
Q

Treatment for Warm AIHA:

A
  • Patients may require red cell transfusions, if they are symptomatic with their anemia
  • However, immunosuppression is the mainstay of therapy.
75
Q

Describe the immunosuppressive treatment common for Warm AIHA patients:

A
  • First line is corticosteroids (i.e. prednisone).
  • If steroids fail to work, or if patient relapses after steroid taper, splenectomy or Rituximab may be necessary.
  • Other immunosuppressives such as may be required as third-line therapy.
76
Q

In patients with Cold Agglutinin Disease, pathogenic antibodies are usually ___, which bind to red cells in the cooler ____ (<32°), then fix complement. When red cells return to the warmer torso, ________.

A

In patients with Cold Agglutinin Disease, pathogenic antibodies are usually IgM, which bind to red cells in the cooler extremities (<32°), then fix complement. When red cells return to the warmer torso, IgM falls off.

77
Q

How are RBCs lysed in patients with Cold Agglutinin Disease?

A
  • Complement-coated red cells can be lysed directly within the vessel (intravascular hemolysis).
  • Alternatively, complement-coated red cells can be engulfed by complement receptors on macrophages within the liver (extravascular hemolysis)
78
Q

In the cold, ____ can lead to red cell agglutination, since it is _____

A

In the cold, IgM can lead to red cell agglutination, since it is pentameric

79
Q

Why do patients with Cold Agglutinin Disease suffer from digital ischemia?

A

Red cells clumps cannot pass through microvasculature, leading to cyanosis and ischemia in extremities

80
Q

Cold Agglutinin Disease can be associated with infection from either ______ or ______

A

IgM - infection with Mycoplasma or Mononucleosis

81
Q

What is the treatment for a patient with Cold Agglutinin Disease?

A
  • Treatment is to keep patient (especially the extremities) warm. Blood and IV fluids should be warmed.
  • Steroids and splenectomy are ineffective.
  • Immunosuppression with other agents such as rituximab may be required.
82
Q

Microangiopathic Hemolytic Anemia:

A

Shear damage to red cells as the result of endothelial cell activation/damage

Hallmark is presence of schistocytes on the peripheral smear

83
Q

What is the cause of Microangiopathic Hemolytic Anemia?

A

Can be caused by the following disorders:

  • TTP/HUS
  • DIC
  • Malignant hypertension
  • Ecclampsia, HELLP syndrome, Acute Fatty Liver of Pregnancy
  • Vasculitis
  • Other, including metastatic cancer, scleroderma renal crisis, solid organ transplant rejection
84
Q

What are the sites of hematopoiesis?

A
  • From birth to 4 years of age hematopoiesis in all marrow cavities;
  • After age 4, bone marrow outgrows need for hematopoiesis;
  • In adults, hematopoiesis in axial skeleton and proximal long bones.
85
Q

What are the essential components of hematopoiesis?

A
  • Stem cells, think of “seeds”;
  • Stromal, think of “soil” (fat cells, macrophages, endothelial cells, and fibroblasts);
  • Growth factors, think of “fertilizer” (cytokines, growth factors, interferons).
86
Q

Non-lineage specific growth factors act on ______ and ______ stem cells to initiate ______ and ________.

List examples.

A

Non-lineage specific growth factors act on pluripotent and multipotent stem cells to initiate self-renewal and differentiation.

IL-3, GM-CSF

87
Q

Lineage specific growth factors act on _________ cells, involved in differentiation and maturation of _________.

List examples

A

Lineage specific growth factors act on committed progenitor cells, involved in differentiation and maturation of blood cells.

G-CSF (granulocyte colony stimulating factor);

M-CSF (monocyte colony stimulating factor);

IL-5 (interleukin-5);

EPO (erythropoietin);

TPO (thrombopoietin).

88
Q

Stem cells comprise _____% of total bone marrow cells:

A
  1. 01-0.05%
    - Also found in small numbers in peripheral blood
89
Q

Pluripotent stem cells (PPSC):

A
  • Self-renewal – proliferate to produce more stem cells.
  • Differentiation – produce highly specialized mature cells types, and from there produce more developmentally restricted cells (progenitor cells).
90
Q

Multipotential Cells:

A

Has the capability of differentiating into either lymphoid or myeloid (non-lymphoid) cells.

91
Q

Progenitor Cells:

A

Committed to a cell lineage. The progressive restriction in developmental potential ensures a tremendous amplification in cell numbers.

92
Q

Precursor Cells:

A

Develop into mature cells of the various cell types and exhibit morphological characteristics specific to their lineage.

93
Q

Iron uptake is influenced by _____; decreases in these will increase absorption

A

Iron stores

94
Q

In the duodenal enterocyte, dietary iron is reduced to the ferrous state by Dcytb, a _________. Ferrous iron is then transported into the _______ by the divalent metal transporter 1 (DMT1)

A

In the duodenal enterocyte, dietary iron is reduced to the ferrous state by Dcytb, a ferric reductase. Ferrous iron is then transported into the enterocyte by the divalent metal transporter 1 (DMT1)

95
Q

Iron leaves the enterocyte and enters the circulation via the action of _______, facilitated by _______

A

Iron leaves the enterocyte and enters the circulation via the action of ferroportin, facilitated by hephaestin

96
Q

Hepatocytes take up iron from the circulation either as ____ iron or _________ iron (through transferrin receptor 1 and transferrin receptor 2).

A

Hepatocytes take up iron from the circulation either as free iron or transferrin-bound iron (through transferrin receptor 1 and transferrin receptor 2).

97
Q

_____ releases iron from the hepatocyte and also macrophages.

A

Ferroportin

98
Q

_______ blocks the action of ferroportin, thus blocking release of iron from the enterocyte, the hepatocyte, and the macrophage into the circulation, thus lowering _____ concentrations.

A

Hepcidin blocks the action of ferroportin, thus blocking release of iron from the enterocyte, the hepatocyte, and the macrophage into the circulation, thus lowering serum iron concentrations.

99
Q

When are Hepcidin levels increased?

A
  • When Tf-bound iron increases
  • By the proteins HFE and hemojuvelin (both mutated in different forms of hereditary hemochromatosis)
100
Q

____ binds to iron in the bloodstream and transports it to cells

A

Transferrin (Tf)

101
Q

What is the total iron binding capacity?

A

This is the amount of iron that Transferrin can bind - about 300 mcg Fe/dL

This goes up with the body iron is deficienct

102
Q

Describe the impact on transferrin when a patient is iron deficient:

A

Total Iron Binding Capacity (TBIC) goes UP

Transferrin Saturation goes DOWN

103
Q

What is Transferrin Saturation?

A

The fraction of available Fe-binding sites which have iron bound to them. This falls as the body becomes iron deficient.

104
Q

Iron is predominantly stored in the protein _____. This level _____ as the body becomes iron deficient.

A

Iron is predominantly stored in the protein Ferritin. This level falls as the body becomes iron deficient.

105
Q

How is iron excreted?

A

There is no regulated excretion of iron. Iron leaves the body only when cells are lost, such as in the following circumstances:

  • Shedding gut and skin epithelial cells-accounts for 1 mg/day in adults
  • Menstruation - 8-72 mg/month
  • Pregnancy—about 1000 mg loss for pregnancy and lactation
  • Blood donation
  • GI blood loss
  • GU loss
106
Q
A
107
Q

For a single unit of blood transfusion into a normal-sized adult, the hemoglobin should rise by ___g/dL

A

1

108
Q

Iron deficiency in adults is almost always due to:

A

blood loss, though there may be a component of malabsorption or dietary insufficiency

109
Q

When does an iron deficient patient become anemic?

A

The body in early iron deficiency will use iron stores before dropping the hemoglobin. Only as iron deficiency becomes more profound will anemia occur.

110
Q

What are three key symptoms seen in iron deficient anemic patients?

A

Pica

Thrombocytosis (elevated platelet count)

Koilonychia (spooning of the nails)

111
Q
A
112
Q

Describe the lab levels for patients with iron deficiency:

A

CBC

  • First sign is elevation of RDW, followed by falling MCV.
  • Hemoglobin and Hematocrit fall last

Ferritin

  • Ferritin levels are measures of iron stores, but can also be elevated with inflammation/infection or liver damage.
  • If ferritin <15, iron deficiency is present
  • In an otherwise healthy outpatient, this is the single best test for iron deficiency.

•Iron studies (includes Fe, Tf, TIBC, %Tf sat)

  • Serum iron falls
  • TIBC increases
  • Transferrin saturation also falls.
113
Q

Physiologic Anemia of Infancy:

A

Hemoglobin and reticulocyte values drop after birth due to the drop in epo production as infants breathe oxygen.

premature infants have a lower nadir (lowest point a blood count will reach) than term infants, due to shorter RBC survival

114
Q

Risk factors for iron deficiency in children:

A

Perinatal risk factors:

  • Maternal iron deficiency
  • Prematurity (One half of the term newborn’s iron stores are laid down in the last month in utero, so premature infants are at markedly increased risk of iron deficiency)
  • Fetal-maternal hemorrhage
  • Insufficient dietary intake during early infancy

Dietary risk factors:

  • Insufficient iron intake
  • Cow’s milk given to children <12 mo old
  • Cow’s milk protein-induced colitis leading to blood loss
115
Q

How can iron deficiency in children be prevented?

A
  • Treat iron deficiency in pregnant and breast-feeding women
  • Encourage breastfeeding exclusively for first 4-6 mo. After four months of age, an additional source of iron should be added, first as an iron supplement, then transitioning to iron-fortified infant cereals
  • For infants <12 mo who are not breastfed or are partially breastfed, use only iron-fortified formulas
  • After age 6 mo, or when developmentally ready, consider introducing pureed meats.
  • Avoid feeding unmodified (nonformula) cow’s milk until age 12 months
  • Children aged one to five years should consume no more than 600 mL (20 oz) of milk per day (risk of iron deficiency increases in young children drinking more than 24 oz of milk per day. Consume an adequate amount of iron-containing foods to meet daily requirements)
116
Q

Iron deficiency in children - sequelae:

A

Neuropsychiatric manifestations:

  • Impaired psychomotor development
  • Cognitive impairment can occur in adolescents
  • Poor infant social-emotional behavior
  • ADHD may increase in severity

Increased risk of thrombosis in infants

Increased risk of lead toxicity:

  • Pica for paint chips
  • Also increased absorption of divalent cations
117
Q

Anemia of Chronic Disease (AOCD):

A

In inflammatory states, cytokines act to sequester iron away from the bloodstream by increasing iron away from the bloodstream by increasing levels of hepcidin.

Serum iron levels fall

TBIC also falls

Ferritin can be normal or elevated

118
Q

Hepcidin acts to:

A
119
Q
  • Decrease iron absorption from gut
  • Decrease iron export out of hepatocytes
  • Decrease transferrin and TIBC
A
120
Q

Compare/contrast lab values in iron deficiency anemia vs. anemia of chronic disease:

A
121
Q

Which of the following individuals should receive iron now:

(note: a normal Hgb is >12, nl MCV is 80-95, ferritin >20)
1. 17 y.o. woman Hgb 7 MCV 65, ferritin 2, elevated TIBC
2. 65 yo man Hgb 9 MCV 70 ferritin 250, low TIBC
3. 2 y.o. girl from Tanzania, Hgb 6, MCV 65, ferritin 12, elevated TIBC
4. 35 y.o. male runner, Hgb 14, MCV 72, ferritin 12, elevated TIBC

A

Patients 1 and 4

122
Q

What are broad categories of hypoproliferative anemia?

A
  • Acute blood loss or destruction
  • Nutritional anemias
  • Bone marrow depression/failure (aplastic anemia)
  • Defective red cell production (myelodysplasia)
  • Destruction of marrow erythroid precursors
  • Replacement of normal bone marrow with something else
123
Q

Nutrients required for erythropoiesis:

A
  • Iron
  • B12 (cobalamine)
  • Folic acid
  • Proteins, amino acids, calories
  • Vitamin B6
  • Vitamin B2 (riboflavin)
  • Niacin
  • Vitamin C
  • Vitamin A
  • Vitamin E
  • Copper
  • Cobalt
124
Q

Define megaloblastic anemia:

A
  • A group of disorders characterized by a defect in DNA synthesis leading to a characteristic morphology of bone marrow cells.
  • Nucleus appears immature, cytoplasm has mature appearance, and increased cell volume is present.
  • B12 and folate deficiency are the most common causes.
125
Q

What do the RBCs look like in patients with megaloblastic anemia?

A

Nucleus appears immature,

cytoplasm has mature appearance, and

increased cell volume is present.

126
Q

______ and ______ are the most common causes of megaloblastic anemias

A

B12 and folate deficiency

127
Q

What are the hematologic and non-hematologic clinical presentations of megaloblastic anemia?

A

Hematologic:

  • Anemia is typically presenting feature
  • MCV is elevated, as is RDW
  • Peripheral smear shows hypersegmented PMNs

Non hematologic:

  • Beefy red smooth tongue (seen with both B12 and folate deficiencies)
  • Neuro/psychiatric features - ONLY seen with B12 deficiency.
128
Q

Folate is needed for ____ synthesis

A

DNA synthesis

129
Q

B12 is necessary for ____ synthesis

A

DNA and myelin

130
Q

How does the body get B12?

A

B12 in diet (found only in animal products) binds to salivary R protein in acidic environment

131
Q

____ cells secrete intrinsic factor (IF)

A

parietal cells

132
Q

Pancreatic enzymes degrade ______, freeing B12

A

R protein

133
Q

IF binds free ____

A

B12

134
Q

B12-IF complex taken up by cells in the ______

A

distal ileum

135
Q

In blood, B12 is carried by ________ to tissues

A

transcobalamin II

136
Q

Causes of B12 deficiency:

A

Inadequate dietary intake e.g. vegan diet (no animal products)

Inadequate absorption:

  • Lack of gastric acid (drugs, atrophic gastritis)
  • Destruction/removal of parietal cells (pernicious anemia, gastrectomy)
  • Gastric Bypass

Reduced B12 absorption in the ileum:

  • Crohn’s disease
  • Sprue (celiac or tropical)
  • Metformin (given for diabetes)

Pancreatic insufficiency

Competition for B12 - fish tapeworm, bacterial overgrowth

Non-functional TCII

Inactivation of cobalamin (nitrous oxide)

137
Q

Describe the neurologic changes associated with B12 deficiency:

A

Classic finding is “subacute combined degeneration of the dorsal (posterior) and lateral spinal columns”

It begins with paresthesias and ataxia associated with loss of vibration and position sense

Can progress to severe weakness, spasticity, clonus, paraplegia, and even fecal and urinary incontinence

Mental status changes, including dementia

Psychiatric findings

138
Q

What are the laboratory findings associated with B12 deficiency?

A

Macrocytosis

Macro-ovalocytes and hypersegmented PMNs on peripheral smear

Can have pancytopenia

With severe deficiency, can have an elevated bili and markedly elevated LDH due to “intramedullary hemolysis”

139
Q

How are B12 deficiencies diagnosed?

A
  • Low B12 level
  • Elevated levels of homocysteine
  • Elevated levels of methylmalonic acid
140
Q

How is B12 deficiency treated?

A
  • B12 deficiency takes years to develop
  • Treat the underlying cause of B12 deficiency, if possible
  • Generally requires intramuscular injections of B12 lifelong
141
Q

How is folic acid absorbed?

A

Folic acid is absorbed throughout small intestine.

No specific transport protein in gut or blood.

142
Q

______ circulation is important for folate absorption. Therefore, ____ drainage causes profoud folate deficiency that occurs in a timeframe of ______.

A

enterohepatic circulation is important for folate absorption. Therefore, biliary drainage causes profoud folate deficiency that occurs in a timeframe of hours.

143
Q

What are the daily folate requirements?

A

•100 mcg for adults

  • 50 mcg for kids (5-10 fold more than adults on wt by wt basis)
  • 400 mcg for pregnant or lactating woman
  • Increased if active cell turnover (hemolysis, psoriasis)
144
Q

Folic acid is stored in the _____ for ______ (timeframe)

A

Stored in the liver for 2-5 months

145
Q

How do patients develop folic acid deficiency?

A
  • Malnutrition - most common cause
  • Malabsorption
  • Drugs can interfere with metabolism
146
Q

How is folate deficiency treated?

A

Treat underlying cause

Oral folate 1-5 mg daily

Extra folate should be given to:

  • Pts with hemolytic anemias
  • Women contemplating pregnancy (prevents neural tube defects).
  • Pregnant/lactating women
147
Q

Who should recieve folate supplementation?

A
  • Pts with hemolytic anemias
  • Women contemplating pregnancy (prevents neural tube defects)
  • Pregnant/lactating women
148
Q

Define aplastic anemia:

A

Pancytopenia in the peripheral blood, with bone marrow biopsy showing hypocellularity (<25%), arising from a deficiency of hematopoietic stem cells

149
Q

What is the etiology of aplastic anemia?

A
  • idiopathic (50%), secondary, and inherited
  • There is definitely an immune component to this disorder, and in many cases, AA is an autoimmune condition
150
Q

What disease is suggested by this image of bone marrow?

A

Aplastic anemia

This image shows numerous fat cells in the bone marrow where instead there should be large numbers of blood cell precursors

151
Q

What are the secondary causes of aplastic anemia?

A

•Ionizing radiation

•Cytotoxic chemotherapy

•Benzene exposure

  • Idiopathic reaction to drugs (chloramphenicol, sulfa drugs, gold salts, NSAIDs, arsenic, anti-epileptics
  • Viruses (EBV, hepatitis(non A, B, C, D, or E))
  • Pregnancy

•Paroxysmal nocturnal hemoglobinuria

  • Thymoma
  • Transfusion-associated graft vs host disease
152
Q

What is the clinical presentation of patients with aplastic anemia?

A

The presentation is caused by deficiencies of the different cell lines:

  • Anemia causes weakness and fatigue and DOE
  • Low platelets cause bruising and oozing
  • Low neutrophil counts can lead to infection and fever

Patients should not have splenomegaly or adenopathy

153
Q

How are aplastic anemias diagnosed?

A

Rule out other causes of pancytopenia:

  • B12/folate deficiency
  • Splenomegaly
  • Other marrow toxins such as alcohol
  • Autoimmune conditions such as lupus
  • Think about exposures to drugs, test for viruses
  • Test for PNH

•Do a bone marrow biopsy

  • Look for degree of cellularity
  • Rule out cancer, infiltrative disorders (like sarcoidosis, fibrosis)
  • Rule out dysplasia (MDS)
154
Q

How are aplastic anemias treated?

A

•Supportive care (transfusions, antibiotics, growth factors)

  • Definitive therapy - stem cell transplantation (used in younger patients with an 80% success rate BUT more toxic)
  • Heavy duty T-cell directed immunosuppression with antithymocyte globulin (ATG) and cyclosporine used in older patients, those without donor match, or heavily pre-transfused. 70-80% successful, but relapses occur.
155
Q

Paroxysmal Nocturnal Hemoglobinuria is an acquired ___ ____ ____.

A

clonal hematologic disorder

156
Q

The abnormal clone in PNH patients is missing the gene for ____, an enzyme that makes a GPI used to anchor several proteins to the cell surface

A

PIG-A

157
Q

PIG-A:

A

an enzyme that makes a GPI (glycosyl-phophosphatidyl-inositol) used to anchor several proteins to the cell surface

158
Q

What types of cells are missing PIG-A proteins on their surface in patients with PNH?

A

red cells, white cells, and platelets

159
Q

Two of the most important GPI anchored proteins are ___ and ____ which are both important for inhibiting complement on the surface of red cells

A

CD55 and CD59

160
Q

PNH cells are abnormally sensitive to WHAT

A

complement-mediated red cell destruction

(because GPI proteins that are unable to form in cells missing the PIG-A gene are important for inhibiting complement on the surface of red cells)

161
Q

Explain the process of red cell destruction in patients with PNH:

A

Red cell destruction (hemolysis) occurs predominantly at night, when the pH falls

The hemolysis leads to free hemoglobin which is then lost in the urine, which will lead to the development of iron deficiency

162
Q

What are the clinical manifestations of PNH?

A

Red cell destruction (hemolysis)

Thrombosis (both arterial and venous) - think Budd Chiari syndrome aka thrombosis of the hepatic veins, leading to hepatic failure

Bone marrow failure

Predisposition to other clonal bone marrow diseases such as MDS and AML

The intravascular hemolysis leads to low NO levels, which leads to a defect in smooth muscle relaxation

163
Q

Intravascular hemolysis leads to low nitric oxide levels, which leads to a defect in smooth muscle relaxation, associated with _____, _____, and _____

A

esophageal spasm

erectile dysfunction

pulmonary hypertension

164
Q

How is PNH treated?

A
  • Treat iron deficiency by repleting iron
  • Treat thrombosis with anticoagulation
  • Treat bone marrow failure by immunosuppression (ATG and cyclosporine) and/or allogeneic stem cell transplantation
  • Treat hemolysis with eculizumab
165
Q

Eculizimab:

A

Used to treat hemolysis in PNH patients:

  • Targets C5 and blocks activation of terminal complement
  • Will thus increase susceptibility to infection with Neisseria organisms (need terminal complement for killing)
  • Treatment is indefinite—
  • And costly—about $600,000 per year.
166
Q

_____ is the most common form of inherited aplastic anemia

A

Fanconi’s anemia

167
Q

What is the inheritance pattern of Fanconi’s Anemia?

A

Autosomal recessive or X-linked

Due to a mutation in one of 16 genes responsible for DNA repair—several of these genes are tumor suppressors

168
Q

What are the clinical manifestations of Fanconi’s anemia?

A
  • Pancytopenia with macrocytic anemia—progressive—may start with just thrombocytopenia
  • Other somatic abnormalities
  • Increased incidence of acute leukemia and solid tumors
  • Usually presents in childhood, but may not be diagnosed until young adulthood
169
Q

Describe the characteristic congenital mutations associated with Fanconi’s Anemia:

A
  • Short stature
  • Hypo-pigmented spots and café-au-lait macules
  • Abnormalities of thumbs and radii
  • Microcephaly or hydrocephaly
  • Hypogonadism
  • Developmental delay
170
Q

Fanconi’s anemia is diagnosed by culturing ______ or fibroblasts with _______ and look for abnormal ____ breakage

A

Fanconi’s anemia is diagnosed by culturing lymphocytes or fibroblasts with diepoxybutane (DEB) and look for abnormal chromosomal breakage

171
Q

What is the treatment of Fanconi’s anemia?

A

allogeneic transplant

with reduced intensity conditioning (pre-transplant), since these patients have abnormal chromosomal sensitivity and are harmed by standard dose chemo/radiation

172
Q

Dyskeratosis congenita is an inherited disorder of _____ involving one of nine genes. Is also an inherited form of _______.

A

Dyskeratosis congenita is an inherited disorder of telomere shortening involving one of nine genes. Is also an inherited form of aplastic anemia.

173
Q

What is the inheritance pattern of Dyskeratosis congenita?

A

May be x-linked, autosomal recessive, or autosomal dominant

174
Q

What is the classic triad of dyskeratosis congenita?

A
  • Mottled hyperpigmentation of skin involving arms, shoulders, neck, torso
  • Abnormal nails of fingers and toes
  • Mucosal leukoplakia
175
Q

What are clinical characteristics associated with Dyskeratosis congenita?

A

•Bone marrow failure

•Predisposition to acute leukemia and other solid tumors (typically squamous cancers)

•Classic triad

  • Mottled hyperpigmentation of skin involving arms, shoulders, neck, torso
  • Abnormal nails of fingers and toes
  • Mucosal leukoplakia

Additional findings:

  • Pulmonary fibrosis
  • Prematurely gray hair
  • Cirrhosis of liver
  • Dental abnormalities
  • Urinary tract abnormalities
  • Immune deficiency
  • Esophageal strictures
  • Osteoporosis
  • hyperhidrosis
176
Q

How is dyskeratosis congenita diagnosed?

A

•Careful history and physical

  • Family history of bone marrow failure and cancers
  • Look for somatic abnormalities
  • Analyze telomere length
  • Genetic analysis (negative results do not rule out disease)
177
Q

What is the treatment for dyskeratosis congenita?

A

Allogeneic transplant, with reduced intensity conditioning (pre-transplant), since these patients have abnormal chromosomal sensitivity and are harmed by standard dose chemo/radiation (they are too susceptible to pulmonary toxicity after exposure to chemo/radiation).

Hematology Block 1 (5 decks)

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